Citation of documents: Please do not cite the URL that is displayed in your browser location input, instead use the DOI, URN or the persistent URL below, as we can guarantee their long-time accessibility.

Abstract

AMPA and NMDA receptors are ionotropic glutamate receptors, respectively sensitive to the glutamate analogue alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) or N-methyl-D-aspartate (NMDA), and are essential for hippocampus-dependent learning and memory. As indicated by global and forebrainspecific mutant mouse models of AMPA and NMDA receptors, distinct molecular mechanisms coexist in the dorsal hippocampus, underlying spatial behavior in working and reference memory tasks. The present study is focused on the main ionotropic glutamate receptors (AMPA receptors with GluR-A or GluR-B subunit or NMDA receptors) in principal neurons (DG, CA1, CA2) of the hippocampus in adult mice and the role of these receptors in spatial working and reference memory. Cre recombinase expression in restricted sublayers of the hippocampal formation and the olfactory system was achieved by the use of transgenes of mouse lines TgCN12-itTA and TgLC1 employing the tet-system to prevent widespread recombination in the mouse embryo. Minor recombination, monitored by the use of gene-targeted Rosa26R mice, accumulated in additional forebrain structures but remained sparsely located in one-year-old mice. By employing the TgCN12-itTA / TgLC1 mouse model to deplete GluR-A in Gria1ΔHipOlf mice, GluR-B in Gria2ΔHipOlf mice or all NMDA receptors by NR1 ablation in Grin1ΔHipOlf mice, excitatory neurotransmission was modified in three major ways. Depletion of these receptor subunits was observed with similar spatial and temporal specificity in hippocampal sublayers of adult mice. With these three iGluRΔHipOlf mouse models in hands, behavioral consequences were investigated in spatial working and reference memory tasks in two independent laboratories (Heidelberg, Germany; Oxford, England). Unexpected from our previous observations (Reisel et al. 2002), GluR-A depleted Gria1ΔHipOlf mice performed well in all cognitive tasks of spatial working behavior independent of delay and task composition. However, Gria1ΔHipOlf mice still expressed hyperactivity in a novel environment and little spontaneous alternation. In contrast, GluR-B depletion in Gria2ΔHipOlf mice became manifest in impairment in spatial working memory. Unfortunately, testing of spatial reference memory in Gria2ΔHipOlf mice is still missing. Grin1ΔHipOlf mice exhibited delay- and task-dependent impairment of the IV spatial working memory and in reversal reference learning. Nevertheless, the acquisition of spatial reference memory in Morris watermaze and Y-maze was not affected upon NR1 depletion in dorsal CA1, CA2 and the entire DG subfield of the hippocampal formation. In summary, genetic manipulation of the main ionotropic glutamate receptors in the three mutant mouse models Gria1ΔHipOlf, Gria2ΔHipOlf and Grin1ΔHipOlf demonstrated the essential role of AMPA receptors containing the GluR-B subunit and NMDA receptors in principal DG, CA1 and CA2 neurons of the hippocampal formation in spatial working memory. Spatial reference memory, however, was still intact upon depletion of AMPA receptors containing the GluR-A subunit in Gria1ΔHipOlf mice and NMDA receptors in Grin1ΔHipOlf mice.